Figure 6

Proposed pro-myogenic role for retinoic acid and Smad3. The bzip transcription factor C/EBPβ is a potent inhibitor of myogenesis. It can stimulate the expression of Pax7 and Smad2 and can autoregulate its own expression. Regulation of Pax7 expression suppresses the myogenic differentiation of myoblasts, while the contribution of Smad2 remains unknown. TGFβ treatment can stimulate C/EBPβ expression during myogenic differentiation, and this contributes in part to the anti-myogenic effects of TGFβ treatment as loss of C/EBPβ partially restores differentiation in the presence of TGFβ. TGFβ can also, upon binding its receptor, stimulate the phosphorylation of both Smad2 and Smad3, and it is known that Smad3 can form inhibitory complexes with myogenic regulatory factors and inhibit myogenesis. Treatment with retinoic acid (RA) can antagonize the effects of TGFβ during myogenesis. In particular, RA can stimulate the expression of Smad3 which in turn associates with C/EBPβ and reduces its occupancy of target gene promoters, resulting in a reduction of their expression and the restoration of differentiation. RA treatment can also prevent the normal phosphorylation of Smad2 by the TGFβ receptor, without affecting Smad3 phosphorylation.